Studies on genetic hemochromatosis and the hepatotoxicity of iron
Author: Hagen, Karin
Date: 2002-06-07
Location: Leksell salen, Medicinhistoriska Museet, Karolinska Sjukhuset
Time: 9.00
Department: Institutionen för medicin / Department of Medicine
Abstract
The aim of this study was to investigate the mutations and clinical
expression of genetic hemochromatosis in patients and mechanisms involved
in the hepatotoxicity of iron in animal and cell- culture models.
In Swedish patients with a clinical diagnosis of genetic hemochromatosis,
the C282Y mutation of the HFE gene was present in 94.2% of chromosomes,
and 92.0% of the patients were homozygous. It is a well-established fact
that the clinical expression of the disease varies. In patients, we
concluded that the amount of body iron stores correlates negatively with
CD8+, a subpopulation of T-lymphocytes, both in peripheral blood and
liver lobuli, and that the lowest counts are seen in patients with
cirrhosis. Thus, apart from genotype, other factors influence the
expression of the disease.
For studies on iron toxicity, an experimental model with rats fed a
carbonyl-iron-enriched diet resulting in hepatic iron overload was used.
In rats fed diets with carbonyl iron followed by ethanol, a synergistic
effect on liver toxicity was seen. When treating rats with
desferrioxamine, serum alanine transferases decreased, showing that the
toxicity was dependant on chelatable iron. The synergistic effect was not
caused by depleted liver glutathione levels, nor by differences in
induction of cytochrome P450 2E1.
As the extracellular matrix undergoes changes in the development of liver
fibrosis with deposition of collagen fibrils, we studied the role of the
extracellular matrix in iron loading, using primary cultures of
hepatocytes from rats fed a diet with carbonyl iron. We compared
hepatocytes plated on a laminin- rich extracellular matrix with
hepatocytes plated on collagen type 1. The rate of lipid peroxidation in
hepatocytes from iron-loaded rats was higher in cells plated on collagen
and when exposed to oxidative stress. When comparing hepatocytes from
iron-loaded rats with hepatocytes from normal rats, cells from
iron-loaded rats were more susceptible to oxidative stress. As lipid
peroxidation diminished when iron was chelated, we concluded that the
combination of iron overload and collagen matrix leads to an increased
susceptibility to oxidative stress.
Since signs of microinflammation are seen in iron-overloaded livers, the
effects of tumour necrosis factor-ct on hepatocytes in culture were
studied. Tumour necrosis factor-alpha increased the synthesis of ferritin
H, decreased the pool of chelatable iron and diminished the
susceptibility to a hydroperoxide. This was true in cells from rats with
a normal iron load, but not in cells from iron- loaded rats. The cytokine
also induced manganese-superoxide dismutase transcription in both cell
types.
In livers from patients with genetic hemochromatosis, expression of the
collagen type I gene and staining for ct-smooth muscle actin was seen as
evidence of hepatic stellate cell activation. When examining a second
liver biopsy after treatment with venesection, a reversal of fibrosis was
observed. The strongest collagen gene expression was observed in livers
from patients investigated shortly after treatment completion.
List of papers:
I. Cardoso EM, Stal P, Hagen K, Cabeda JM, Esin S, de Sousa M, Hultcrantz R (1998). "HFE mutations in patients with hereditary haemochromatosis in Sweden. " J Intern Med 243(3): 203-8
Pubmed
II. Cardoso EM, Hagen K, de Sousa M, Hultcrantz R (2001). "Hepatic damage in C282Y homozygotes relates to low numbers of CD8+ cells in the liver lobuli. " Eur J Clin Invest 31(1): 45-53
Pubmed
III. Stal P, Johansson I, Ingelman-Sundberg M, Hagen K, Hultcrantz R (1996). "Hepatotoxicity induced by iron overload and alcohol. Studies on the role of chelatable iron, cytochrome P450 2E1 and lipid peroxidation. " J Hepatol 25(4): 538-46
Pubmed
IV. Hagen K, Zhu C, Melefors O, Hultcrantz R (1999). "Susceptibility of cultured rat hepatocytes to oxidative stress by peroxides and iron. The extracellular matrix affects the toxicity of tert-butyl hydroperoxide. " Int J Biochem Cell Biol 31(3-4): 499-508
Pubmed
V. Hagen K, Eckes K, Melefors O, Hultcrantz R (2002). "Iron overload decreases the protective effect of tumor necrosis factor-alpha on rat hepatocytes exposed to oxidative stress." Scand J Gastroenterol (In Print)
VI. Hagen K, Garuti C, Montosi G, Stal P, Lindholm J, Hultcrantz R, Pietrangelo A (2002). "Effects of iron removal on fibrosis in genetic hemochromatosis." (Manuscript)
I. Cardoso EM, Stal P, Hagen K, Cabeda JM, Esin S, de Sousa M, Hultcrantz R (1998). "HFE mutations in patients with hereditary haemochromatosis in Sweden. " J Intern Med 243(3): 203-8
Pubmed
II. Cardoso EM, Hagen K, de Sousa M, Hultcrantz R (2001). "Hepatic damage in C282Y homozygotes relates to low numbers of CD8+ cells in the liver lobuli. " Eur J Clin Invest 31(1): 45-53
Pubmed
III. Stal P, Johansson I, Ingelman-Sundberg M, Hagen K, Hultcrantz R (1996). "Hepatotoxicity induced by iron overload and alcohol. Studies on the role of chelatable iron, cytochrome P450 2E1 and lipid peroxidation. " J Hepatol 25(4): 538-46
Pubmed
IV. Hagen K, Zhu C, Melefors O, Hultcrantz R (1999). "Susceptibility of cultured rat hepatocytes to oxidative stress by peroxides and iron. The extracellular matrix affects the toxicity of tert-butyl hydroperoxide. " Int J Biochem Cell Biol 31(3-4): 499-508
Pubmed
V. Hagen K, Eckes K, Melefors O, Hultcrantz R (2002). "Iron overload decreases the protective effect of tumor necrosis factor-alpha on rat hepatocytes exposed to oxidative stress." Scand J Gastroenterol (In Print)
VI. Hagen K, Garuti C, Montosi G, Stal P, Lindholm J, Hultcrantz R, Pietrangelo A (2002). "Effects of iron removal on fibrosis in genetic hemochromatosis." (Manuscript)
Issue date: 2002-05-17
Publication year: 2002
ISBN: 91-7349-201-9
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